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Jul 17, 2014

Gene Therapy Yields Biological Pacemakers

  • Cedars-Sinai Heart Institute scientists report the development of a minimally invasive gene transplant procedure that changes unspecialized heart cells into biological pacemaker cells that keep the heart steadily beating. The lab animal research study ("Biological pacemaker created by minimally invasive somatic reprogramming in pigs with complete heart block"), published in Science Translational Medicine, is the result of a dozen years of research with the goal of developing biological treatments for patients with heart rhythm disorders who currently are treated with surgically implanted pacemakers, according to Eduardo Marbán, M.D., Ph.D., director of the Institute. In the U.S., an estimated 300,000 patients receive pacemakers every year.

    "We have been able, for the first time, to create a biological pacemaker using minimally invasive methods and to show that the biological pacemaker supports the demands of daily life," said Dr. Marbán, who led the research team. "We also are the first to reprogram a heart cell in a living animal in order to effectively cure a disease."

    The team’s findings could lead to clinical trials for humans who have heart rhythm disorders but who suffer side effects from implanted mechanical pacemakers, such as infection of the leads that connect the device to the heart, he added.

    Eugenio Cingolani, M.D., the director of the Institute's Cardiogenetics-Familial Arrhythmia Clinic who worked with Dr. Marbán on the biological pacemaker research team, said that in the future pacemaker cells also could help infants born with congenital heart block.

    "Babies still in the womb cannot have a pacemaker, but we hope to work with fetal medicine specialists to create a life-saving catheter-based treatment for infants diagnosed with congenital heart block," noted Dr. Cingolani. "It is possible that one day we might be able to save lives by replacing hardware with an injection of genes."

    "This work team heralds a new era of gene therapy, in which genes are used not only to correct a deficiency disorder, but to actually turn one kind of cell into another type," said Shlomo Melmed, M.D., dean of the Cedars-Sinai faculty and the Helene A. and Philip E. Hixson Distinguished Chair in Investigative Medicine.

    In the study, laboratory pigs with complete heart block were injected with the gene called TBX18 during a minimally invasive catheter procedure. On the second day after the gene was delivered to the animals' hearts, pigs who received the gene had significantly faster heartbeats than pigs who did not receive the gene. The stronger heartbeat persisted for the duration of the 14-day study.

    "We…tested whether adenoviral TBX18 gene transfer could create biological pacemaker activity in vivo in a large-animal model of complete heart block," wrote the investigators. "Relative to controls transduced with a reporter gene, TBX18-transduced animals exhibited enhanced autonomic responses and physiologically superior chronotropic support of physical activity. Induced sinoatrial node cells could be identified by their distinctive morphology at the site of injection in TBX18-transduced animals, but not in controls. No local or systemic safety concerns arose. Thus, minimally invasive TBX18 gene transfer creates physiologically relevant pacemaker activity in complete heart block, providing evidence for therapeutic somatic reprogramming in a clinically relevant disease model."

    "Originally, we thought that biological pacemaker cells could be a temporary bridge therapy for patients who had an infection in the implanted pacemaker area," explained Dr. Marbán. "These results show us that with more research, we might be able to develop a long-lasting biological treatment for patients."

    If future research is successful, the procedure could be ready for human clinical studies in about three years, according to Dr. Marbán.


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